Skip to main content
Log in

GABA-ergic Inhibition in the CNS: Types of GABA Receptors and Mechanisms of Tonic GABA-Mediated Inhibitory Action

  • Published:
Neurophysiology Aims and scope

Abstract

This review considers such aspects of the problem of GABA-ergic inhibition in the CNS as the fundamental molecular mechanisms of GABA-ergic synaptic transmission, current questions on the principles underlying the classification of the GABA receptors, the diversity of the types of GABA-ergic inhibition, as well as possible mechanisms and functional importance of the tonic GABA-mediated inhibitory action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. E. A. Barnard, P. Skolnick, R. W. Olsen, et al., “International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function,” Pharmacol. Rev., 50,No. 2, 291-313 (1998).

    Google Scholar 

  2. Y. C. Chen, S. S. Kung, B. Y. Chen, et al., “Identifications, classification, and evolution of the vertebrate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit genes,” J. Mol. Evol., 53,No. 6, 690-702 (2001).

    Google Scholar 

  3. J. J. Soghomonian and D. L. Martin, “Two isoforms of glutamate decarboxylase: why?” Trends Pharmacol. Sci., 19,No. 12, 500-505 (1998).

    Google Scholar 

  4. E. M. Fykse and F. Fonnum, “Amino acid neurotransmission: dynamics of vesicular uptake,” Neurochem. Res., 21,No. 9, 1053-1060 (1996).

    Google Scholar 

  5. S. Takamori, J. S. Rhee, C. Rosenmund, et al., “Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons,” Nature, 407,No. 6801, 189-194 (2000).

    Google Scholar 

  6. E. E. Bellocchio, R. J. Reimer, R. T. Fremeau, Jr., et al., “Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter,” Science, 289,No. 5481, 957-960 (2000).

    Google Scholar 

  7. F. A. Chaudhry, R. J. Reimer, E. E. Bellocchio, et al., “The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABA-ergic neurons,” J. Neurosci., 18,No. 23, 9733-9750 (1998).

    Google Scholar 

  8. A. Schousboe, “Pharmacological and functional characterization of astrocytic GABA transport: a short review,” Neurochem. Res., 25,Nos. 9/10, 1241-1244 (2000).

    Google Scholar 

  9. M. P. Kavanaugh, J. L. Arriza, R. A. North, et al., “Electrogenic uptake of gamma-aminobutyric acid by a cloned transporter expressed in Xenopusoocytes,” J. Biol. Chem., 267,No. 31, 22007-22009 (1992).

    Google Scholar 

  10. J. N. Cammack, S. V. Rakhilin, and E. A. Schwartz, “A GABA transporter operates asymmetrically and with variable stoichiometry,” Neuron, 13,No. 4, 949-960 (1994).

    Google Scholar 

  11. J. Bormann, “The ‘ABC’ of GABA receptors,” Trends Pharmacol. Sci., 21,No. 1, 16-19 (2000).

    Google Scholar 

  12. E. Costa, “From GABAAreceptor diversity emerges a unified vision of GABA-ergic inhibition,” Annu. Rev. Pharmacol. Toxicol., 38,No. 321–350 (1998).

    Google Scholar 

  13. A. K. Mehta and M. K. Ticku, “An update on GABAAreceptors,” Brain Res.-Brain Res. Rev., 29,Nos. 2/3, 196-217 (1999).

    Google Scholar 

  14. M. T. Bianchi, K. F. Haas, and R. L. Macdonald, “Structural determinants of fast desensitization and desensitization-deactivation coupling in GABAa receptors,” J. Neurosci., 21,No. 4, 1127-1136 (2001).

    Google Scholar 

  15. Z. Nusser, W. Sieghart, D. Benke, et al., “Differential synaptic localization of two major gamma-aminobutyric acid type A receptor alpha subunits on hippocampal pyramidal cells,” Proc. Natl. Acad. Sci. USA, 93,No. 21, 11939-11944 (1996).

    Google Scholar 

  16. A. R. Brooks-Kayal, M. D. Shumate, H. Jin, et al., “Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy,” Nat. Med., 4,No. 10, 1166-1172 (1998).

    Google Scholar 

  17. G. Sperk, C. Schwarzer, K. Tsunashima, et al., “GABA(A) receptor subunits in the rat hippocampus I: immunocytochemical distribution of 13 subunits,” Neuroscience, 80,No. 4, 987-1000 (1997).

    Google Scholar 

  18. C. Essrich, M. Lorez, J. A. Benson, et al., “Postsynaptic clustering of major GABAAreceptor subtypes requires the gamma 2 subunit and gephyrin,” Nat. Neurosci., 1,No. 7, 563-571 (1998).

    Google Scholar 

  19. R. L. Macdonald and R. W. Olsen, “GABAAreceptor channels,” Annu. Rev. Neurosci., 17,No. 569–602 (1994).

    Google Scholar 

  20. C. Rivera, J. Voipio, J. A. Payne, et al., “The K+/Clco-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation,” Nature, 397,No. 6716, 251-255 (1999).

    Google Scholar 

  21. K. Ganguly, A. F. Schinder, S. T. Wong, et al., “GABA itself promotes the developmental switch of neuronal GABA-ergic responses from excitation to inhibition,” Cell, 105,No. 4, 521-532 (2001).

    Google Scholar 

  22. Y. Ben-Ari, V. Tseeb, D. Raggozzino, et al., “Gamma-aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life,” Prog. Brain Res., 102,No. 261–273 (1994).

    Google Scholar 

  23. M. F. Jackson, B. Esplin, and R. Capek, “Activity-dependent enhancement of hyperpolarizing and depolarizing gamma-aminobutyric acid (GABA) synaptic responses following inhibition of GABA uptake by tiagabine,” Epilepsy Res., 37,No. 1, 25-36 (1999).

    Google Scholar 

  24. S. Smirnov, P. Paalasmaa, M. Uusisaari, et al., “Pharmacological isolation of the synaptic and nonsynaptic components of the GABA-mediated biphasic response in rat CA1hippocampal pyramidal cells,” J. Neurosci., 19,No. 21, 9252-9260 (1999).

    Google Scholar 

  25. G. A. Johnston, “GABAAreceptor pharmacology,” Pharmacol. Ther., 69,No. 3, 173-198 (1996).

    Google Scholar 

  26. B. Schonrock and J. Bormann, “Functional heterogeneity of hippocampal GABAAreceptors,” Eur. J. Neurosci., 5,No. 8, 1042-1049 (1993).

    Google Scholar 

  27. D. B. Pritchett, H. Luddens, and P. H. Seeburg, “Type I and type II GABAA-benzodiazepine receptors produced in transfected cells,” Science, 245,No. 4924, 1389-1392 (1989).

    Google Scholar 

  28. M. Eghbali, P. W. Gage, and B. Birnir, “Pentobarbital modulates gamma-aminobutyric acid-activated single-channel conductance in rat cultured hippocampal neurons,” Mol. Pharmacol., 58,No. 3, 463-469 (2000).

    Google Scholar 

  29. H. Mohler and J. M. Fritschy, “GABABreceptors make it to the top as dimers,” Trends Pharmacol. Sci., 20,No. 3, 87-89 (1999).

    Google Scholar 

  30. K. A. Jones, B. Borowsky, J. A. Tamm, et al., “GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2,” Nature, 396,No. 6712, 674-679 (1998).

    Google Scholar 

  31. R. Kuner, G. Kohr, S. Grunewald, et al., “Role of heteromer formation in GABABreceptor function,” Science, 283,No. 5398, 74-77 (1999).

    Google Scholar 

  32. A. Couve, S. J. Moss, and M. N. Pangalos, “GABABreceptors: a new paradigm in G protein signaling,” Mol. Cell Neurosci., 16,No. 4, 296-312 (2000).

    Google Scholar 

  33. D. D. Mott and D. V. Lewis, “The pharmacology and function of central GABABreceptors,” Int. Rev. Neurobiol., 36, 97-223 (1994).

    Google Scholar 

  34. J. M. Fritschy, V. Meskenaite, O. Weinmann, et al., “GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization,” Eur. J. Neurosci., 11,No. 3, 761-768 (1999).

    Google Scholar 

  35. M. Scanziani, “GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity,” Neuron, 25,No. 3, 673-681 (2000).

    Google Scholar 

  36. D. R. Hill, N. G. Bowery, and A. L. Hudson, “Inhibition of GABABreceptor binding by guanyl nucleotides,” J. Neurochem., 42,No. 3, 652-657 (1984).

    Google Scholar 

  37. M. Nishikawa, M. Hirouchi, and K. Kuriyama, “Functional coupling of Gisubtype with GABABreceptor/adenylyl cyclase system: analysis using a reconstituted system with purified GTP-binding protein from bovine cerebral cortex,” Neurochem. Int., 31,No. 1, 21-25 (1997).

    Google Scholar 

  38. I. M. Mintz and B. P. Bean, “GABABreceptor inhibition of P-type Ca2+channels in central neurons,” Neuron, 10,No. 5, 889-898 (1993).

    Google Scholar 

  39. R. Anwyl, “Modulation of vertebrate neuronal calcium channels by transmitters,” Brain Res.-Brain Res. Rev., 16,No. 3, 265-281 (1991).

    Google Scholar 

  40. U. Misgeld, M. Bijak, and W. Jarolimek, “A physiological role for GABABreceptors and the effects of baclofen in the mammalian central nervous system,” Prog. Neurobiol., 46,No. 4, 423-462 (1995).

    Google Scholar 

  41. R. Andrade, R. C. Malenka, and R. A. Nicoll, “A G protein couples serotonin and GABABreceptors to the same channels in hippocampus,” Science, 234,No. 4781, 1261-1265 (1986).

    Google Scholar 

  42. J. Bormann and A. Feigenspan, “GABACreceptors,” Trends Neurosci., 18,No. 12, 515-519 (1995).

    Google Scholar 

  43. D. Zhang, Z. H. Pan, M. Awobuluyi, et al., “Structure and function of GABA(C) receptors: a comparison of native versus recombinant receptors,” Trends Pharmacol. Sci., 22,No. 3, 121-132 (2001).

    Google Scholar 

  44. R. Enz, J. H. Brandstatter, E. Hartveit, et al., “Expression of GABA receptor rho 1 and rho 2 subunits in the retina and brain of the rat,” Eur. J. Neurosci., 7,No. 7, 1495-1501 (1995).

    Google Scholar 

  45. K. Wegelius, M. Pasternack, J. O. Hiltunen, et al., “Distribution of GABA receptor rho subunit transcripts in the rat brain,” Eur. J. Neurosci., 10,No. 1, 350-357 (1998).

    Google Scholar 

  46. R. Enz and G. R. Cutting, “GABACreceptor rho subunits are heterogeneously expressed in the human CNS and form homo-and heterooligomers with distinct physical properties,” Eur. J. Neurosci., 11,No. 1, 41-50 (1999).

    Google Scholar 

  47. T. Ogurusu, K. Yanagi, M. Watanabe, et al., “Localization of GABA receptor rho 2 and rho 3 subunits in rat brain and functional expression of homooligomeric rho 3 receptors and heterooligomeric rho 2 rho 3 receptors,” Receptors Channels, 6,No. 6, 463-475 (1999).

    Google Scholar 

  48. A. S. Hackam, T. L. Wang, W. B. Guggino, et al., “Sequences in the amino termini of GABA rho and GABA(A) subunits specify their selective interaction in vitro,” J. Neurochem., 70,No. 1, 40-46 (1998).

    Google Scholar 

  49. P. Koulen, J. H. Brandstatter, R. Enz, et al., “Synaptic clustering of GABA(C) receptor rho-subunits in the rat retina,” Eur. J. Neurosci., 10,No. 1, 115-127 (1998).

    Google Scholar 

  50. H. Qian and H. Ripps, “Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA rho-and gamma 2-subunits,” Proc. Roy. Soc. Lond., Ser. B, Biol. Sci., 266,No. 1436, 2419-2425 (1999).

    Google Scholar 

  51. Y. Momose-Sato, K. Sato, A. Hirota, et al., “Optical characterization of a novel GABA response in early embryonic chick brainstem,” Neuroscience, 80,No. 1, 203-219 (1997).

    Google Scholar 

  52. K. L. Perkins and R. K. Wong, “Ionic basis of the postsynaptic depolarizing GABA response in hippocampal pyramidal cells,” J. Neurophysiol., 76,No. 6, 3886-3894 (1996).

    Google Scholar 

  53. T. F. Freund and A. I. Gulyas, “Inhibitory control of GABA-ergic interneurons in the hippocampus,” Can. J. Physiol. Pharmacol., 75,No. 5, 479-487 (1997).

    Google Scholar 

  54. T. F. Freund and G. Buzsaki, “Interneurons of the hippocampus,” Hippocampus, 6,No. 4, 347-470 (1996).

    Google Scholar 

  55. M. Scanziani, B. H. Gahwiler, and S. Charpak, “Target cell-specific modulation of transmitter release at terminals from a single axon,” Proc. Natl. Acad. Sci. USA, 95,No. 20, 12004-12009 (1998).

    Google Scholar 

  56. R. Miles, K. Toth, A. I. Gulyas, et al., “Differences between somatic and dendritic inhibition in the hippocampus,” Neuron, 16,No. 4, 815-823 (1996).

    Google Scholar 

  57. J. C. Poncer, R. A. McKinney, B. H. Gahwiler, et al., “Either N-or P-type calcium channels mediate GABA release at distinct hippocampal inhibitory synapses,” Neuron, 18,No. 3, 463-472 (1997).

    Google Scholar 

  58. S. G. Brickley, S. G. Cull-Candy, and M. Farrant, “Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAAreceptors,” J. Physiol., 497,No. 3, 753-759 (1996).

    Google Scholar 

  59. M. J. Wall and M. M. Usowicz, “Development of action potential-dependent and independent spontaneous GABAAreceptor-mediated currents in granule cells of postnatal rat cerebellum,” Eur. J. Neurosci., 9,No. 3, 533-548 (1997).

    Google Scholar 

  60. P. A. Salin and D. A. Prince, “Spontaneous GABAAreceptor-mediated inhibitory currents in adult rat somatosensory cortex,” J. Neurophysiol., 75,No. 4, 1573-1588 (1996).

    Google Scholar 

  61. Q. Y. Liu, J. Vautrin, K. M. Tang, et al., “Exogenous GABA persistently opens Cl-channels in cultured embryonic rat thalamic neurons,” J. Membrane Biol., 145,No. 3, 279-284 (1995).

    Google Scholar 

  62. T. S. Otis, K. J. Staley, and I. Mody, “Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release,” Brain Res., 545,Nos. 1/2, 142-150 (1991).

    Google Scholar 

  63. D. Bai, G. Zhu, P. Pennefather, et al., “Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons,” Mol. Pharmacol., 59,No. 4, 814-824 (2001).

    Google Scholar 

  64. C. Bernard, R. Cossart, J. C. Hirsch, et al., “What is GABA-ergic inhibition? How is it modified in epilepsy?” Epilepsia, 41,No. 6, S90-S95 (2000).

    Google Scholar 

  65. R. Cossart, C. Dinocourt, J. C. Hirsch, et al., “Dendritic but not somatic GABA-ergic inhibition is decreased in experimental epilepsy,” Nat. Neurosci., 4,No. 1, 52-62 (2001).

    Google Scholar 

  66. R. Cossart, R. Tyzio, C. Dinocourt, et al., “Presynaptic kainate receptors that enhance the release of GABA on CA1hippocampal interneurons,” Neuron, 29,No. 2, 497-508 (2001).

    Google Scholar 

  67. R. S. Fisher and B. E. Alger, “Electrophysiological mechanisms of kainic acid-induced epileptiform activity in the rat hippocampal slice,” J. Neurosci., 4,No. 5, 1312-1323 (1984).

    Google Scholar 

  68. A. Rodriguez-Moreno, O. Herreras, and J. Lerma, “Kainate receptors presynaptically downregulate GABA-ergic inhibition in the rat hippocampus,” Neuron, 19,No. 4, 893-901 (1997).

    Google Scholar 

  69. I. Soltesz, D. K. Smetters, and I. Mody, “Tonic inhibition originates from synapses close to the soma,” Neuron, 14,No. 6, 1273-1283 (1995).

    Google Scholar 

  70. D. J. Rossi and M. Hamann, “Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry,” Neuron, 20,No. 4, 783-795 (1998).

    Google Scholar 

  71. H. L. Gaspary, W. Wang, and G. B. Richerson, “Carrier-mediated GABA release activates GABA receptors on hippocampal neurons,” J. Neurophysiol., 80,No. 1, 270-281 (1998).

    Google Scholar 

  72. Q. Y. Liu, A. E. Schaffner, Y. H. Chang, et al., “Persistent activation of GABA(A) receptor/Cl-channels by astrocyte-derived GABA in cultured embryonic rat hippocampal neurons,” J. Neurophysiol., 84,No. 3, 1392-1403 (2000).

    Google Scholar 

  73. L. S. Overstreet and G. L. Westbrook, “Paradoxical reduction of synaptic inhibition by vigabatrin,” J. Neurophysiol., 86,No. 2, 596-603 (2001).

    Google Scholar 

  74. J. Lerma, A. S. Herranz, O. Herreras, et al., “In vivodetermination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis,” Brain Res., 384,No. 1, 145-155 (1986).

    Google Scholar 

  75. B. Birnir, A. B. Everitt, M. S. Lim, et al., “Spontaneously opening GABA(A) channels in CA1pyramidal neurones of rat hippocampus,” J. Membrane Biol., 174,No. 1, 21-29 (2000).

    Google Scholar 

  76. B. Birnir, M. Eghbali, A. B. Everitt, et al., “Bicuculline, pentobarbital and diazepam modulate spontaneous GABA(A) channels in rat hippocampal neurons,” Br. J. Pharmacol., 131,No. 4, 695-704 (2000).

    Google Scholar 

  77. T. R. Neelands, J. L. Fisher, M. Bianchi, et al., “Spontaneous and gamma-aminobutyric acid (GABA)-activated GABA(A) receptor channels formed by epsilon subunit-containing isoforms,” Mol. Pharmacol., 55,No. 1, 168-178 (1999).

    Google Scholar 

  78. M. Hausser and B. A. Clark, “Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration,” Neuron, 19,No. 3, 665-678 (1997).

    Google Scholar 

  79. B. Cauli, J. T. Porter, K. Tsuzuki, et al., “Classification of fusiform neocortical interneurons based on unsupervised clustering,” Proc. Natl. Acad. Sci. USA, 97,No. 11, 6144-6149 (2000).

    Google Scholar 

  80. A. R. Granata, “Effects of gamma-aminobutyric acid on putative sympatho-excitatory neurons in the rat rostral ventrolateral medulla in vitro. Intracellular study,” Neurosci. Lett., 300,No. 1, 49-53 (2001).

    Google Scholar 

  81. D. Cattaert and A. El Manira, “Shunting versus inactivation: analysis of presynaptic inhibitory mechanisms in primary afferents of the crayfish,” J. Neurosci., 19,No. 14, 6079-6089 (1999).

    Google Scholar 

  82. M. F. Jackson, B. Esplin, and R. Capek, “Inhibitory nature of tiagabine-augmented GABAAreceptor-mediated depolarizing responses in hippocampal pyramidal cells,” J. Neurophysiol., 81,No. 3, 1192-1198 (1999).

    Google Scholar 

  83. C. R. Shields, M. N. Tran, R. O. Wong, et al., “Distinct ionotropic GABA receptors mediate presynaptic and postsynaptic inhibition in retinal bipolar cells,” J. Neurosci., 20,No. 7, 2673-2682 (2000).

    Google Scholar 

  84. Z. H. Pan, “Voltage-activated Ca2+channels and ionotropic GABA receptors localized at axon terminals of mammalian retinal bipolar cells,” Vis. Neurosci., 18,No. 2, 279-288 (2001).

    Google Scholar 

  85. C. A. Hubner, V. Stein, I. Hermans-Borgmeyer, et al., “Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition,” Neuron, 30,No. 2, 515-524 (2001).

    Google Scholar 

  86. Z. Nusser, W. Sieghart, and P. Somogyi, “Segregation of different GABAAreceptors to synaptic and extrasynaptic membranes of cerebellar granule cells,” J. Neurosci., 18,No. 5, 1693-1703 (1998).

    Google Scholar 

  87. S. G. Brickley, V. Revilla, S. G. Cull-Candy, et al., “Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance,” Nature, 409,No. 6816, 88-92 (2001).

    Google Scholar 

  88. F. Duprat, F. Lesage, M. Fink, et al., “TASK, a human background K+channel to sense external pH variations near physiological pH,” EMBO J., 16,No. 17, 5464-5471 (1997).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Semyanov, A.V. GABA-ergic Inhibition in the CNS: Types of GABA Receptors and Mechanisms of Tonic GABA-Mediated Inhibitory Action. Neurophysiology 34, 71–80 (2002). https://doi.org/10.1023/A:1020274226515

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020274226515

Navigation